ABSTRACT Autonomic failure is a group of rare neurodegenerative disorders that primarily affect the autonomic nervous system. There are two main subtypes: 1) MSA in which autonomic impairment is combined with an extrapyramidal or cerebellar movement disorder or both, and 2) PAF in which autonomic impairment occurs alone. Supine norepinephrine (NE) levels (normal in MSA and low in PAF) failed to increase upon standing. This leads to impaired sympathetic-mediated vasoconstriction that results in neurogenic orthostatic hypotension (NOH), cerebral hypoperfusion and symptoms such as lightheadedness, dizziness, syncope and falls that contributes to morbidity, disability and death in this population. I hypothesized that the pharmacological agent, atomoxetine, a norepinephrine transporter (NET) blocker that increases the availability of NE at the level of the synapse by blocking its reuptake, could induce an increase in blood pressure and be a potential treatment for NOH in autonomic failure. In normal individuals, atomoxetine has minimal hemodynamic effects because of a balance between its central and peripheral actions on the autonomic nervous system. In central autonomic pathways, the increased NE levels diminish sympathetic activity by stimulating ?-2 adrenergic receptors. In peripheral sympathetic fibers, the increased NE levels may stimulate sympathetic activity by acting on postganglionic ?-1 adrenergic receptors. Patients with autonomic failure have an imbalance between these central and peripheral autonomic pathways. In MSA, the peripheral sympathetic fibers are disconnected from its central input unmasking any peripheral sympathetic- like effect and blood pressure response. In a proof-of-concept clinical trial, I determined the effect of 18 mg of atomoxetine on seated and standing blood pressure in 21 autonomic failure patients (10 MSA and 11 PAF). These preliminary data showed that an acute dose of 18 mg of atomoxetine increased seated systolic blood pressure (SBP) by ~50 mm Hg compared with placebo in MSA only. In a separate crossover study, we compared the effect of a single dose of 18 mg of atomoxetine with midodrine (5,10 mg) and placebo on standing SBP and clinical symptoms in 69 patients with NOH and autonomic failure. Our results showed that atomoxetine and midodrine increased seated BP at the same magnitude. However, 18 mg of atomoxetine was more effective than midodrine in improving standing SBP (+7.5 mm Hg). The response to an acute administration of a pressor agent, however, does not predict the long-term efficacy of the drug. We propose to test the hypothesis that prolonged (4-week) administration of the NET blocker, atomoxetine, improves clinical symptoms, activities of daily living, and increases standing blood pressure in patients with MSA and early MSA.